1. Field of the Invention
The present invention relates to compositions for supporting bone marrow transplantation.
2. Description of the Background
Factors for differentiating mature B cells into antibody-producing cells in humans and mice are collectively called B cell differentiation factor (BCDF).
Human BCDF possesses activity which is important in the human body. Extensive research work in the recent past has led to the determination of the DNA sequence coding for BCDF and of the amino acid sequence of BCDF (Japanese Patent Application OPI Nos. 42688/88 and 56291/88). Further, human BCDF has been successfully produced using E. coli (Japanese Patent . Application OPI No. 157996/88).
It has been found that human BCDF can be used as an immunotherapeutic agent which is effective in the treatment of infectious diseases and cancers (Japanese Patent Application No. 289007/87). However, there has been no report in the literature of any pharmaceutical effects which human BCDF exhibits when it is administered in support of bone marrow transplantation (bone marrow transplantation is an effective treatment for diseases of hematopoietic organs such as leukemia, aplastic anemia, and the like).
Alternatives to the term human BCDF such as BSF-2 or interleukin 6 (IL-6) have been proposed (Nature, 324, 73 (1986), EMBO. J., 6, 1219 (1987)). In the present text, however, the conventional term BCDF is used. Further, human BCDF as used herein does not possess interferon activity and is thus different from the IFN-.beta..sub.2 standard which has interferon activity (European Patent Application Laid Open No. 0220574).
It is known that bone marrow contains multipotential hematopoietic stem cells (hereinafter identified as stem cells), although their quantity in bone marrow is small. These cells have the ability to differentiate into an all blood cell system, including lymphocytes. At the same time they also have self-renewal ability.
Blood cells have a limited life span. But the timely death of a blood cell is compensated for by the production of new blood cells. Stem cells in bone marrow maintain a constant number of blood cells in an organism through their self-renewal ability and continuing differentiation.
Therefore, where an abnormality in the quality of stem cells in an organism occurs for some reason, normal blood cell production is adversely affected. This causes irreversible desolation in the hematopoietic ability or immune capability of the organism.
The technique of bone marrow transplantation is used to transplant normal bone marrow cells, in which stem cells are present, into an organism to combat such a morbid state.
Deficient or diseased cells are replaced with cells derived from the normal. stem cells thereby curing the particular disease.
In 1951, Lorenz et al gave the theoretical basis for clinical application of bone marrow transplantation for the first time, reporting that the administration of bone marrow cells protected mice and guinea pigs exposed to lethal total-body irradiation (J.N.C.I., 12, 197 (1951)).
In recent years, bone marrow transplantation has been used to treat various intractable hematopoietic diseases including leukemia and severe aplastic anemia. Many successful results have been reported. However, a limited number of patients participate in the benefits of this technique because the therapy is not safe and sure for all patients so treated (TAISHYA, 21, 899 (1984)). This is because numerous treated patients die due to serious complications caused by the transplantation itself, notwithstanding that various preventive measures are taken to protect the patient.
Major complications include graft versus host disease (hereafter simply referred to as GVHD), serious infections and interstitial pneumonia. For example, in the case of leukemia, death was observed in 202 out of 356 cases over the 10 year period of 1975 to 1985. A major cause of these deaths was the above stated complications, in spite of the fact that the patients received bone marrow transplantation (TAISHYA, 24, extra volume, GANN '87, 205 (1987)).
Why bone marrow transplantation is accompanied by the complications described above is as follows. In a patient suffering from leukemia, or the like, who receives bone marrow transplantation, the count of all leucocytes including malignant and normal leucocytes is reduced to zero by irradiation prior to the bone marrow transplantation operation. Irradiation is then followed by transplantation of bone marrow cells. After malignant leucocytes are eradicated by this operation, normal bone marrow cells are transplanted. The transplanted bone marrow cells function by producing a sufficient number of normal leucocytes. However, various complications such as infectious diseases occur during this time period up to when the transplanted bone marrow cells begin to function satisfactorily, namely, at the stage when normal leucocyte counts are reduced.
Therefore, a fundamental problem is how hematological and immunological reconstruction can be accelerated after bone marrow transplantation. Various supporting therapies such as the use of sterile rooms with sterile food, intestinal sterilization, constituent blood transfusion, and the like are normally employed upon bone marrow transplantation. In fact, attention has been directed to a recent development which is the clinical application of biologically active substances which act on the immune capability or hematopoiesis.
Other methodologies include the application of granulocyte colony stimulating factor (G-CSF) and urine-derived colony stimulating factor (CSF-HU) (Nippon Rinsho, 45, 2769 (1987)). However, the actions of these factors are mainly based on the differentiation of cells into mature granulocytes or monocytes.
Compositions and method for supporting bone marrow transplantation which are capable of causing the replication of stem cells which can accelerate hematological and immunological reconstruction important for bone marrow transplantation are yet unknown. A need therefore continues to exist for such a method.